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A Randomized Phase I/II Study of Bortezomib, Rituximab, Dexamethasone and Temsirolimus in Patients With Relapsed Waldenstrom`s Macroglobulinemia and Relapsed/Refractory Mantle Cell, Follicular, Marginal Zone or Small Lymphocytic Lymphomas (Phase I), andUntreated/Relapsed Waldenstrom's Macroglobulinemia (Phase II)


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Cognitive/Functional Effects, Fatigue, Neurotoxicity, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Small Lymphocytic Lymphoma, Therapy-related Toxicity, Waldenström Macroglobulinemia

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Trial Information

A Randomized Phase I/II Study of Bortezomib, Rituximab, Dexamethasone and Temsirolimus in Patients With Relapsed Waldenstrom`s Macroglobulinemia and Relapsed/Refractory Mantle Cell, Follicular, Marginal Zone or Small Lymphocytic Lymphomas (Phase I), andUntreated/Relapsed Waldenstrom's Macroglobulinemia (Phase II)


PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of temsirolimus in combination with
bortezomib, rituximab, dexamethasone in patients with relapsed Waldenstrom's
Macroglobulinemia and relapsed/refractory mantle cell, follicular, marginal zone or small
lymphocytic lymphoma. (Phase I) II. To evaluate whether the addition of temsirolimus to the
regimen of bortezomib, rituximab, dexamethasone improves progression-free survival in
patients with previously untreated or relapsed Waldenstrom's Macroglobulinemia. (Phase II)

SECONDARY OBJECTIVES:

I. To define and describe the toxicities of temsirolimus in combination with bortezomib,
rituximab, and dexamethasone. (Phase I) II. To evaluate time to progression of bortezomib,
rituximab, dexamethasone +/- temsirolimus in patients. (Phase II) III. To evaluate major and
minor response by 6 cycles of therapy of bortezomib, rituximab, dexamethasone +/-
temsirolimus. (Phase II) IV. To evaluate time to response and duration of response of
bortezomib, rituximab, dexamethasone +/- temsirolimus. (Phase II) V. To evaluate toxicity of
bortezomib, rituximab, dexamethasone +/- temsirolimus. (Phase II) VI. To evaluate time to
next therapy of bortezomib, rituximab, dexamethasone +/- temsirolimus. (Phase II) VII. To
evaluate overall survival of bortezomib, rituximab, dexamethasone +/- temsirolimus. (Phase
II) VIII. To describe treatment-related fatigue, physical and functional well-being during
and after treatment. (Phase II) IX. To compare the change in treatment related fatigue,
physical and functional well-being over 6 cycles of bortezomib, rituximab, dexamethasone +/-
temsirolimus. (Quality of Life) X. To prospectively assess health-related quality of life
longitudinally (pre-treatment to 3 year follow-up assessment) among trial participants.
(Quality of Life) XI. To describe treatment-related peripheral neuropathy associated with
bortezomib neurotoxicity. (Quality of Life)

OUTLINE: This is a multicenter, phase I, dose-escalation study of temsirolimus followed by a
phase II study.

PHASE I: Patients receive temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22;
rituximab IV over 30-60 minutes on days 1, 8, 15, and 22 (of courses 1 and 4 only); and
bortezomib IV and dexamethasone orally (PO) on days 1, 8, and 15. Courses repeat every 28
days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are stratified according to disease status (previously untreated vs
relapsed) and by the International Prognostic Scoring System for Waldenstrom
macroglobulinemia staging (stage I or II vs stage III). Patients are randomized to 1 of 2
treatment arms.

ARM I: Patients receive rituximab intravenously (IV) over 30-60 minutes on days 1, 8, 15,
and 22 (of courses 1 and 4 only) and bortezomib IV and dexamethasone orally (PO) on days 1,
8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease
progression or unacceptable toxicity.

ARM II: Patients receive temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22 and
rituximab, bortezomib, and dexamethasone as in arm I. Treatment repeats every 28 days for 6
courses in the absence of disease progression or unacceptable toxicity.

Patients complete the Functional Assessment of Cancer Therapy (FACT) Physical well-being
scale, the Functional well-being scale, and the FACT-Fatigue scale at baseline and
periodically during study.

After completion of study therapy, patients are followed up every 3 months for 2 years,
every 6 months for 5 years, and then yearly for 5 years.


Inclusion Criteria:



- Histologically proven diagnosis of relapsed Waldenstrom macroglobulinemia, relapsed
mantle cell, follicular lymphoma, relapsed marginal zone lymphoma, or relapsed small
lymphocytic lymphoma previously treated with at least one standard regimen and no
longer responding to that regimen (phase I)

- Histologically proven diagnosis of symptomatic Waldenstrom macroglobulinemia, either
untreated or relapsed, confirmed by the presence of all of the following (phase II):

- Bone marrow lymphoplasmacytosis with >= 10% lymphoplasmatic cells (measured
within 28 days prior to registration) OR aggregates or sheets of one of the
following:

- Lymphocytes

- Plasma cells

- Lymphoplasmacytic cells on the bone marrow biopsy

- Measurable disease defined as a quantitative IgM monoclonal protein of ≥ 1000
mg/dL

- Cluster of differentiation 20 (CD20)-positive bone marrow or lymph node by
immunohistochemistry or flow cytometry

- Lymph node biopsy must be done =< 28 days prior to registration if used as an
eligibility criterion for study entry

- Serum protein electrophoresis (SPEP) is required to be performed within 28 days
prior to registration

- In addition to measurable disease, patients must have symptomatic disease defined by
one or more of the following:

- Laboratory studies defining eligibility (Hgb, platelet count, viscosity) must
have been obtained within 28 days prior to registration; if more than one test
was obtained, the most recent one will be utilized

- Hemoglobin =< 11 g/dL

- Hyperviscosity syndrome or measured viscosity level of >= 4 centipoise

- NOTE: For these patients it is strongly recommended that they undergo
therapeutic plasmapheresis prior to initiation of therapy

- Platelet count < 100,000/MM^3

- Symptomatic lymphadenopathy, splenomegaly, or hepatomegaly

- Constitutional symptoms including fever, night sweats, or unexplained weight
loss (at least 10% of body weight in < 6 months)

- Symptomatic cryoglobulinemia

- Additional requirements for Waldenstrom's macroglobulinemia (WM) patients (Phase I):

- Patients must have received previous treatment with at least one standard
regimen and are no longer responsive to that regimen

- If last regimen is with rituximab there must have been at least 6 months since
last rituximab dose, and if without rituximab there must have been at least 3
months since last regimen

- Additional requirements for WM patients (Phase II):

- For previously treated patients, no more than 4 prior regimens are allowed

- If last regimen is with rituximab there must have been at least 6 months since
last rituximab dose, and if without rituximab there must have been at least 3
months since last regimen

- Patients must not be receiving concurrent steroids > 10mg prednisone (or equivalent)
per day

- Prior irradiation is allowed if >= 28 days prior to registration have elapsed since
the date of last treatment

- Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =<
2.5 x institutional upper limit of normal (ULN), within 28 days prior to registration

- NOTE: In case one or both of these thresholds are exceeded, the patient can only
be included after initiation of appropriate lipid lowering medication; patients
cannot be enrolled if they do not meet these criteria on or off lipid lowering
medication; patients must start lipid lowering medication and cholesterol and
triglycerides must be below said levels before study entry

- Patients must not have had prior exposure to mammalian target of rapamycin (m-TOR)
inhibitors (sirolimus, temsirolimus, everolimus)

- Women must not be pregnant or breast-feeding due to the fact that the reproductive
risk to humans taking temsirolimus is unknown; all females of childbearing potential
must have a blood test or urine study within 2 weeks prior to registration to rule
out pregnancy; a female of childbearing potential is any woman, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the following
criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has
not been naturally postmenopausal for at least 24 consecutive months (i.e., has had
menses at any time in the preceding 24 consecutive months)

- Women of childbearing potential and sexually active males must use an accepted and
effective method of contraception throughout the study and for 8 weeks following
discontinuation of everolimus

- Patients must have no history of prior malignancy except for adequately treated basal
cell or squamous cell skin cancer or in-situ cervical cancer; the patient may also
have had other cancer for which the patient was curatively treated with surgery alone
and from which the patient has been disease free for >= 5 years

- Platelets >= 75,000mm^3

- Neutrophils >= 1,000mm^3

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5
x institutional ULN

- Direct bilirubin =< 1.5 mg/dL

- Serum creatinine =< 2.5 mg/dL

- Patients must be tested for hepatitis B surface antigen (HBsAg) and hepatitis B core
antibody (anti-HBc) within 28 days of registration and will not be eligible if found
to be positive

- Patients must not have any severe and/or uncontrolled medical condition or other
conditions that could affect their participation in the study, including, but not
restricted to:

- Symptomatic congestive heart failure of New York Heart Association class III or
IV

- Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction within 3 months of start of study treatment, serious uncontrolled
cardiac arrhythmia or any other clinically significant heart disease

- Severely impaired lung function as defined as spirometry and diffusing capacity
of the lung for carbon monoxide (DLCO) (corrected for Hgb) that is < 50% of the
normal predicted value and/or oxygen (O2) saturation < 88% at rest on room air

- Active (acute or chronic) or uncontrolled severe infections

- Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of =<
2

- Patients must not have grade 2 or higher neuropathy

- Patients must not have concurrent use of angiotensin-converting enzyme (ACE)
inhibitors (angioedema), and no concurrent use of strong cytochrome P450, family 3,
subfamily A, polypeptide 4 (CYP3A4) inducers and inhibitors

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD and recommended phase II dose of temsirolimus in combination with bortezomib, rituximab, and dexamethasone (Phase I)

Outcome Description:

Dose-limiting toxicity (DLT) is based on the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).

Outcome Time Frame:

Up to 6 courses

Safety Issue:

Yes

Principal Investigator

Leonard Heffner

Investigator Role:

Principal Investigator

Investigator Affiliation:

Eastern Cooperative Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-02650

NCT ID:

NCT01381692

Start Date:

July 2011

Completion Date:

Related Keywords:

  • Cognitive/Functional Effects
  • Fatigue
  • Neurotoxicity
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Small Lymphocytic Lymphoma
  • Therapy-related Toxicity
  • Waldenström Macroglobulinemia
  • Fatigue
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Lymphoma
  • Lymphoma, Follicular
  • Waldenstrom Macroglobulinemia
  • Neurotoxicity Syndromes
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Mantle-Cell

Name

Location

Mayo ClinicRochester, Minnesota  55905
Fox Chase Cancer CenterPhiladelphia, Pennsylvania  19111
Geisinger Medical CenterDanville, Pennsylvania  17822-0001
Marshfield ClinicMarshfield, Wisconsin  54449
Emory UniversityAtlanta, Georgia  30322
Presbyterian - Saint Lukes Medical Center - Health OneDenver, Colorado  80218
Marshfield Clinic-Minocqua CenterMinocqua, Wisconsin  54548
Gundersen LutheranLa Crosse, Wisconsin  54601